PT93009A - PROCESS FOR THE PREPARATION OF NEW ARIL- OR HETEROARIL-1-ALKYL-PYRROLE-2-CARBOXYLIC ACIDS IN THE TREATMENT OF SITUACOES MEDIATED BY INTERLEUCIN-1 - Google Patents

Description

MERBELLDQW.PHÔBÍJÁCIUIICÍLS-INQi

" PROCESS FOR THE PREPARATION OF NEW ARIL- OR HETEROARIL-1-EQUAL-PYRROL-2-CARBOXYLIC ACIDS

Useful in the treatment of situations mediated by INTERLEUCIN-1 "

Background of the Invention Interleukin-1 refers to a family of molecules secreted by stimulated macrophages that affect multiple biologic responses. Interleukin-1 activities are summarized in Murphy, British Journal of Rheumatology, 24 (Supplement 1) (1985) 6-9, and Oppenheim et al., Immunology Today, 2, (1986) 45--55, 1 depicted as a mediator of T lymphocyte proliferation and the acute phase response of inflammation, also demonstrates pyrogent and pro-inflammatory actions. Interleukin-1 induces connective tissue changes and has been shown to induce the release of (1985), 25-28, Payer, Britt, et al., "Immunohistochemistry for the treatment of rheumatoid arthritis". , J. Rheumatology, 24 (Supplement 1) (1985) 15-20, k Droducing proteins in the acute phase in bepathocytes during the acute phase of inflammation is mediated by IL-1, Whicher, Brit, J, Rheumatology, 24 Supplement 1} (1985) 21-24, -2-

Interleukin-1 also acts as a mediator in inflammatory skin disease, psorTase, Camp, et al., ≪ 3, Immunology, 137 (1986), 3469-3474 and Ri'stWo? (1987) 1940-1944. It has a cytotoxic action on the insulin-producing cells of the pancreas and is thus a causative factor in the development of some forms of diabetes melitus Bendtzen, et al., Science, 2321 (1986), 1545-1 547 and Marx, Science, 239 (1988) 257-258. Interleukin-1 taabem appears to be involved in the development of atherosclerotic lesions or plaques. Marx, Science, 239 (1988), 257-258. Interleukin-1 stimulates the development and proliferation of smooth muscle cells in vascular tissue, an effect that is increased in the absence or suppression of endogenous prostaglandins, which can lead (1988) 487-498, therefore, it is advantageous to control the release of interleukin-1 and conditions mediated by interleukin -1 such as inflammation, psoriasis, diabetes and atherosclerosis,

There is also a need to control or treat interleukin-1-induced inflammation without producing concomitant desirable effects presently accompanying the use of sterile amphipathic agents and non-steroidal anti-inflammatory agents,

The present invention relates to certain aryl- and heteroacids

COOH tert-arylalkyl-pyrrole-carboxylic acids of general formula

In which X represents a phentyl, naphthyl or Biphenyl group each optionally having one, two or three substituents selected from C1-4 alkyl groups, with the proviso that the chain does not represent or when X represents a unsubstituted fentyl radical; or X represents a thiophenyl or furanyl group, each of these groups optionally having one or more substituents selected from C 1-4 alkyl groups, provided that the C 3 chain is not a Z 2 group when X represents an unsubstituted 2-furanyl radical; And salts thereof. Compounds of formula I which may be used as effective inhibitors of interferon-1, alleviating conditions mediated by interleukin-1,

As used herein, the term refers to straight or branched alkyl chains consisting of one to six carbon atoms and which include groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like, such as vinyl, aryl, propynyl, butyl, butadienyl, isopropenyl, etc.,

The aryl and heteroaryl groups falling within the scope of the present invention [X] may each be attached to a chain on any available carbon atom of the aryl or heteroaryl nucleus. In addition, when X contains one, two or three substituent groups , the substituent (s) may be located at any of the free positions of the nucleus. When X has more than one substituent, each substituent is chosen independently from the other (s) so that the various substituents may be the same or different.

The optional substituent C1 -C6 alkyl groups are straight or branched chain alkyl groups having one to four carbon atoms and include the appropriate groups previously assigned to the C1-6 alkyl chain.

Illustrative examples of the compounds of the present invention include; 1- (2-furanylmethyl) -1H-pyrrol-2-carboxylic acid; 1- (phenylmethyl) -1H-pyrrole-1-carboxylic acid, 1- (1,1'-biphenyl] -4-ylmethyl] -1H-pyrrol- 2-carboxamide; 1- [6- (2-Furanyl) hexyl] -1H-pyrrole-2-carboxylic acid; 1- (2-naphthylmethyl) -1H-pyrrole-2-carboxylic acid; 1- (2-methylphenyl) -1H-indole-2-carboxylic acid; -1H-pyrrole-1-carboxylic acid; 1-oxo-5,5-ethoxyphenylmethyl] -1H-pyrrole-2-carboxylic acid;

Scheme 1-C3 -phenylmethyl-1H-pyrrol-2-carboxylic acid; 1-[(5-phenethyl) -1H-pyrazine-2-carboxylic acid] -1- [2,6-tritymethoxy] methyl] -N-methyl ester; (4,41-dimethyl) -4-methyl-3- (ethyl) -4H-indole carboxylate Acidic acid acid Acid acid Acid 6- (2'-dimethylnaphthylmethyl) -1H-pyrrole-2-carboxylic acid [1, 2-carboxylic acid tert-butyl ester; 1 - [3- (2-methyl-furanylmethyl) -1 H -pyrrole-1-carboxylic acid 1- [3- (3-methoxyphenyl) methoxy-1-thienyl] -1H-pyrazole-4-carboxylic acid 1- [3- (3-methoxyethoxybutyl) -1H-pyrazole-2- (3-methoxy-17-naphthyl) pent-1 H -pyrrolo [1,2-a] carboxylic acid 1- [4- (3-ethoxy) -11-phenylethyl] -4- (4-methoxyphenyl) -1H-pyrazole- 11-yl) -1H-pyrrole-2-carboxylic acid; 1- (4-Fluoro-2-oxoethyl) -1,1-biphenyl-4-ylmethyl] -2- 1- (2-hexyl) phenyl] methyl-1H-pyrrole-2-carboxylic acid 1- (2-furanyl) ethyl 1 H -pyrrole-2-carboxylic acid 1- (4-t-butylphenoxy) -1H-pyrrole-2-carboxylic acid,

As with most classes of compounds with therapeutic activity, certain subclasses and certain species which are especially effective are preferred to others. In this regard, compounds of formula I in which there is a chain of one, two or three carbon atoms between the group represented by X and the group ptrrole and wherein X does not bear substituents. Most preferred compounds are those in which X represents an unsubstituted furanyl or substituted biphenyl group attached to the pyrrolyl nucleus by a methyl,

The compounds of formula I are prepared according to the procedure outlined in Reaction Scheme I,

REACTION CHART I 2,5-dimethoxytetrahydropyran

Ctnj

(IV) wherein X has the above defined meaning for the general formula Γ and Y and Y 'have the following meaning,

Fundamentally, Reaction Scheme I shows that the compounds of formula I can easily be prepared by

(refluxing) with 2,5-dimethoxytetrahydrofuran and glacial acetic acid to give X-alkyl pyrrole (III), or by reaction of the pyrrole (in dimethylacetamide) with a compound (11), wherein Y represents a chlorine, bromine or iodine atom, or a mesylate or tosylate group), to give a compound III which is then , the acetyl pyrrole IV compound is converted by means of a conventional Friedel-Krafts acylation with a compound of general formula (in which Y 'represents a fluorine, chlorine or bromine atom), which in then it is refluxed with sodium hydroxide or with potassium hydroxide and water and finally, the compound is acidified with an acid such as malonic acid, hydrochloric acid or acetic acid to give the compounds of general formula I .

The specific examples which follow are presented to elucidate the synthesis of the compounds of this invention, but should not be construed as limiting their scope in any way.

Example 1 1- (2-Furanylmethyl) -1H-pyrrole-2-carboxylic acid

5.0 g (51.5 mmol) furfurylamine, 6.8 g (51.5 mmoles) 2,5-dimethoxytetrahydrofuran and 50 g (51.5 mmol) of sodium methoxide were charged to a 100 ml round bottom flask equipped with a reflux condenser. ml glacial acetic acid. The flask was heated under reflux for 90 minutes and then evaporated to dryness under reduced pressure to give 8.5 g of a dark oil. The oil was distilled on a Kugelrohr apparatus and evaporated to dryness. the fraction which distilled between 50 ° C and 70 ° C was collected at a pressure of 0.1 mm Hg to give 4.9 g of T-furfurylpyrrole as an oil,

2.3 g (15.6 mmol) of 1-furfurylpyrrole, 15 ml of trifluoroacetic anhydride (22.35 g, 106 mmol), 50 ml of n-methyl ethane and 25 ml of diethyl ether were introduced into a round bottom flask The mixture was stirred overnight under argon atmosphere.The reaction mixture was warmed and the excess solvents were removed by distillation. The mixture was evaporated to dryness under reduced pressure to give 3 , 9 g of a dark oil which was distilled on a Kugelrohr apparatus. The fraction which distilled between 80 ° C and 90 ° C was collected at a pressure of 0.2 mmHg to give 3.0 g of a colorless oil , 1- (2-furanyl) methyl] -2-trifluoroacetyl-1H-pyrrole This oil was added to 50 ml of ethyl alcohol in a 100 ml round bottom flask equipped with a reflux condenser, the reaction mixture was cooled to 0 ° C and 3.0 g of sodium hydride was added in 15 ml of water, and the reaction mixture was refluxed for 3 hours. Ethan ol by distillation and 50 ml of water was added. The mixture was cooled and acidified by the addition of 5.0 g of malonic acid. A precipitate formed which was collected by filtration. The solid precipitate in acetonitrile to provide the title compound as a white powder, mp 117-118 ° C, infrared absorption spectrum at 34 ° C cm-1, 1675 cm-1, 153 ° C, cm -1, 750 cm -1,

In a similar manner, but replacing the above furfurylamine by the following starting compounds and following the procedure described in example I, the following compounds were prepared: 1-Amino-3-furfuryl amine (or 3-furanylmethyl amine ) to give 1- (3-furanylmethyl) -1H-pyrrole-2-carboxylic acid, 2-thiophenemethylamine to give 1- (2-thienylmethyl) -1H-pyrrol- 4-methyl-2-thiophenemethylamine was obtained to give 1- (4-methyl-1-phenylmethyl) -1H-pyrrol-2-carboxylic acid, 4, of 3- (3-furanylpropyl) amine to provide 1- (3-furanylpropyl) -1H-pyrrole-2-carboxylic acid, 5-Amino-4-methoxy-2-furanylmethylamine 1- (2- (4-metyl) furanylmethyl) -1H-pyrrol-2-carboxylic acid.

Example 2

1- (Phenylmethyl) -1H-pyrrole-2-carboxylate:

In a round-bottomed flask equipped with a reflux condenser, 10.7 g (0.1 mole) of benzylamine, 13.2 g (0.1 mole) of 2,5- The reaction mixture was refluxed for two hours and then evaporated to dryness under reduced pressure on a rotary evaporator to give 18.0 g of an oily residue, The Oil was distilled in a Kugelrhor apparatus at 85øC to 120øC at a pressure of 0.25 mm Hg to provide 11.5 g (73% yield) of 1-benzyl-1H-pyrrole,

A 100 ml round-bottom flask was allowed to stand where 3.1 g (20 mmol) of 1-benzyl-1H-pyrrole, 7.4 g (24 mmol) of trichloroacetic anhydride and 50 ml of anhydrous diethyl ether and allowed to stand at room temperature overnight, whereupon the mixture was evaporated to dryness under reduced pressure to provide 5.0 g of 1-benzyl-2-chloroacetyl-1H-pyrrole The title compound was prepared as a yellow solid in a 250 ml round-bottomed flask and the 5.0 g of the oil was charged with 100 ml of ethanol (ethyl alcohol). The mixture was refluxed and then refluxed. , 3.0 g of sodium hydroxide in 15 ml of water was added. The reaction mixture was refluxed for 2 hours and then diluted with 50 ml of water. The mixture was partitioned between ethyl acetate and dichloromethane in an ice bath and then acidified by the addition of 5.0 g of malonic acid. The mixture was then extracted with diethyl ether in a 500 ml separatory funnel. the ethereal phase with water and saturated sodium chloride solution. The ether phase was filtered over sodium sulfate and evaporated to dryness under reduced pressure to give 2.8 g of a brown crystalline solid. The solid was recrystallised from Acetonitrile to give 1.3 g of white flocculent crystals of the title compound. Mp 1300 ° C at 133 ° C,

In a similar manner, but substituting benzyl! the following starting compounds and following the procedure described in Example 2, the following compounds can be prepared: 1. 3-phenyl-1-propylamine is obtained to provide 1- [3-phenylpropyl -1H-pyrrole-2-carboxylic acid. 2. Part of N -butylbenzylamine is obtained to give 1-Z '[4-butyl] phenylmethyl] -1 H -pyrrole-2-carboxylic acid. 3. Part O-hexylbenzylamine yields 1- [1- (2-heptyl) phenylmethyl] -1 H -pyrrole-2-carboxylic acid,

Example 3

1-ZTl-11-biphenyl-4-ylmethyl- H-β-pyrrole-2-carboxylate

To a 100 ml round bottom flask was charged 3.4 g (51 mmol) pyrrole, 2% sodium hydrogen chloride 60% in oil (51 mmol) and dimethylacetamide (50 ml) which were kept under stirring. at room temperature for 2 hours. 10.1 [50 mmol of p-phenylbenzyl chloride was added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was then heated on a steam bath for 2 hours. The mixture was diluted with water and diethyl ether. The phases were separated in a 500 ml separatory funnel. The ether layer was washed with water and filtered through sodium sulfate, then evaporated to dryness under reduced pressure to give 12.2 g of a solid mixture. The mixture was crystallized from acetonitrile to give 5.7 g of the starting phenylbenzyl chloride. Evaporation of the remaining liquid under reduced pressure gave 6.5 g of a semi-solid product,

6.5 g of 1- (1-phenylbenzyl) -1H-pyrrole were charged into 50 ml of diethyl ether and 10 ml of trichloroacetic anhydride in a round-bottomed flask and the solution was allowed to stand at ambient temperature for The reaction mixture was then evaporated to dryness under reduced pressure to give a residue which was dissolved in 200 ml of ether. The ether phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The ether phase was filtered through sodium sulfate and evaporated to dryness to give 9.0 g of a dark oil ,

The oil was refluxed in 100 ml of ethanol and 5.8 g of sodium methoxide was added in 25 ml of water. The reaction mixture was refluxed for 2 hours, cooled, was treated with 5.0 g of malonic acid. The precipitate was extracted with ether and the ether evaporated to dryness to give 7.2 g of yellowish powder. This powder was recrystallized from acetonitrile to give 4- 2 g of the title compound as a pale yellow powder, mp 190 ° C,

In a similar manner, but substituting the following starting compounds for the following starting compounds following the procedure described in Example 3, the following compounds can be prepared by substituting the p-nitrobenzyl chloride for the above-mentioned benzyl compound: of 2-naphthylmethyl chloride to provide the 1-C2-naphthylmethyl-1 H -pyrrole-2-carboxylic acid, 2 part of 4- [1 ', 1', 2'-biphenyl- butyl ester to give the acid! -Ζ4-ΖΌ > 1-biphenyl-4-yl] -hexyl] -4 H -pyrrole-2-carboxylic acid, 3, 5-phenylpiperidine hydrochloride To provide 1-quinolylphenylacetic acid -1H-pyrrole-2-carboxylic acid, 4-Amino-4-fluoro-4-fluoro-4- 1,1'-biphenyl-4-ylmethyl] -1H-pyrrole- The title compound was prepared from 1-methyl-2-naphthylmethyl chloride to provide 1-O-methyl-2-naphthylmethyl-1 H -pyrrole-2-carboxylic acid

The compounds of the present invention are useful both in the form of free acids and in the form of salts, the expression is " pharmaceutically acceptable salt " refers to an organic acid addition salt of any of the compounds of general formula I, salts which are relatively non-toxic and harmless to a patient, at concentrations consistent with efjt activity

So that the side effects attributed to the salt do not invalidate the beneficial effects of the base compounds of formula I. These salts are within the scope of the invention. These salts include the ammonium salts, metal salts alkaline, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts of organic bases such as, for example, dicyclohexylamine salts, N-methyl-D-glucamine and amino acid salts such as arginine and lysine; etc. Physiologically compatible non-toxic salts are preferred, although other salts are also usable for, for example, the isolation and purification of the product or as investigational compounds.

The salts are obtained by conventional means such as by reaction of the product as the free acid with one or more equivalents of the appropriate base in a solvent or medium in which the salt is insoluble, or in a solvent such as Water then is removed under vacuum or by lyophilization, or else by exchanging the cations of an existing salt by another cation on an appropriate tonic exchange resin,

Compounds of the general formula I as effective inhibitors of interleukin-1 to alleviate conditions mediated by interleukin-1. Usually, they are administered to a mammal to control the secretion of interleukin 1, control the effects mediated by interleukin 1, or to control the inflammation mediated by interleukin-1, in an amount effective to produce a response of interleukin 1, One response is a measurable effect produced as a result of administration of the compound. The compounds are administered to treat or treat conditions mediated by; interleukin-1 such as inflammation, pseudo-rhythm, atherosclerosis and diabetes,

The interleukin-1 receptor properties of the compounds of the present invention can readily be determined by known standard procedures. For example, the following procedure was used to demonstrate the inhibitory activity of terleukin-1,

Mice were given orally 100. mg / kg of test compounds at 4, 24 and 16 hours before sacrifice, after which peritoneal cells were pelleted and agglomerated and washed by centrifugation. Cells were resuspended in RMP-1640 medium containing antibiotics and plated, after one hour incubation at 37 ° C, the non-adherent cells were removed, and RMPI medium was added to each well, with or without 1-polyisocyanates. The presence of lipopolysaccharides will induce the secretion of TNFα by the macrophages. After incubation for six hours, the culture supernatant is collected, filtered and stored until further analysis,

Mouse thymocytes were suspended in RPMI enriched with fetal bovine serum and 2-mercaptoethanol. Aliquots of the cell suspension were incubated with an equal volume of dilutions of macrophages cultured in the presence of a suboptimal amount of phyto- hemagglutinin for 72 hours in 3 flat bottom plates. Hyro-cultures were labeled with H-thymidine for at least 16 hours, and harvested by means of glass filters, the H-thymidine and incorporated into the DNA of actively proliferating cells, Determined the radioactivity was counted by liquid scintillation counting and the activity of interleukin-1 was expressed in units defined as the inverse of the dilution required to provide 50% of the maximal H-timidtin incorporation,

The effects of the compounds of general formula I as benzyl. of interleukin-1 are shown in Table 1, TABLE 1

Inhibition of excretion of interleukin-1 secretion by macrophages' n. v

Compound Interleukin-1 units / ml Mean + DMP (n)% Inhibition 1 10.2 +/- 3.4 93.2 control 149.4 +/- 35.5 2. 171.3 +/- 7.9. 67.4 control 526.1 +/- 55.5 x. - 3 26.6 +/- 3.9 94.9 control 526.1 + / 65.5

The compounds were administered at a dose of 100 mg / kg, p.o., 3 times (40, 24 and 16 hours prior to sacrifice).

Compound 1: 1- (2-furanylmethyl) -1-methyl-carboxylic acid

Compound 2: 1- (phenylmethyl) -1H-pyrrole-2-carboxylic acid

Compound 3: 1- (Π, 1'-biphenyl-4-ylmethyl) -1H-pyrrole-2-carboxylic acid

The results quoted above indicate that significant inhibition of the release of interleukin-1 was obtained with the test compounds.

A patient for the purposes of the present invention is a mammal, including a human, in need of treatment for a given condition of injury or disease. The amount of active ingredient (i.e., a compound of formula I ] to be administered to the patient for the treatment of interleukin-1 mediated conditions may vary greatly according to considerations such as the particular dosage unit used, the time of treatment, the age and sex of the patient to be treated and the nature and extent of the condition being treated.

The compounds of the present invention are used to provide the desired pharmacological effect upon administration to a patient of appropriately formulated pharmaceutical composition using standard parenteral, oral or topical dosage unit forms or the like. The total amount of active ingredient to be administered intravenously generally ranges from about 0.1 mg / kg to about 30 mg / kg and is preferably between 1.0 mg / kg and 10.0 mg / kg. A dosage unit may contain between 5 and 525 mg of active ingredient, and may be administered one or more times per day. For example, a patient weighing 50 kg may be administered between 50 mg and 700 mg of active ingredient four times daily for a total dose of 200 to 2,800 mg per day. The total amount of active ingredient a administered orally in the range of about 1.0 mg / kg to 100 mg / kg and preferably between 1.0 mg / kg and 50 mg / kg. A dosage unit may contain from 5 to 1,000 mg of active 4 mg active tooth and may be administered. one or more times a day. For example, a 50 kg patient may administer 50 to 2,500 mg of active ingredient four times a day making a total of 200 to 10,000 mg per day. The total amount of active ingredient present in a topical composition varies generally, from 0.01% to 15% (by weight / volume) of the pharmaceutical composition, The preferred amount of ingredients. active agent is in the range of 1% to 10% (by weight / volume). of the pharmaceutical composition. Generally, a topical composition may be applied one or more times per day or it may be administered in the form of a controlled release preparation wherein the active ingredient in a single dose is released for one or more days.

For oral administration, the compounds are formulated in the form of solid or liquid compositions, such as capsules, pills, tablets, troches, lozenges, powders, solutions, suspensions or emulsions, according to any known conventional method for the preparation of compositions pharmaceutical companies. Solid dosage unit forms may be a capsule which may be comprised of hard gelatin or soft gelatin containing, for example, surface active agents, lubricating agents and inert fillers such as lactose, sucrose, calcium phosphate and corn starch. In a further aspect, the compounds of the present invention may be compressed with conventional compression bases such as lactose, sucrose or corn starch, in association with binders such as acacia, corn starch or gelatin, for the disintegration and dissolution of tablets after administration, such as potato starch, alginic acid, corn starch and guar gum, lubricating agents intended to improve the flow of grams. (dies ") and punctures, for example, talc, stearic acid or magnesium, calcium or zinc stearate, coloring agents and flavoring agents intended to improve the aesthetic qualities of the tablets to render them more acceptable to the patient. Suitable excipients for use in liquid oral dosage forms include solvents such as water and alcohols, for example ethanol, benzyl alcohol and polyethylene alcohols, with or without the addition of surfactants, suspending agents or emulsifying agents acceptable from the point of view pharmaceutical.

The compounds of the present invention may also be administered parenterally, i.e. subcutaneously, intravenously, intramuscularly or intraperitoneally as an in-

of the compounds in a physiologically acceptable solvent with a pharmaceutical carrier which may be comprised of a sterile liquid or a mixture of sterile liquids such as water, sodium chloride solution, aqueous dextrose or sugar solutions like alcohols such as ethanol, isopropanol, hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers such as polyethylene glycol ] 400, an oil, a fatty acid, a fatty acid ester or glyceride, or a glyceride of acetylated fatty acids with or without addition of pharmaceutically acceptable surfactants such as a soap or a detergent, suspending agents such as pectin , carotene, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents or other pharmaceutical adjuvants, which may be used in the compositions p The present inventories are petroleum derivatives, oils of animal, vegetarian or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, milfto oil, olive oil, petroleum jelly, and petroleum jelly. Mineral oils, Suitable fatty acids include oleic acid, stearic acid and isostearic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristanate. Suitable soaps include the alkali metal, ammonium and triethanolamine fatty salts and suitable detergents include cationic detergents, for example, dimethyl dialkylammonium phthalides, alkyl pyridinium phthalides and the like. alkyl amine acetates; anionic detergents, for example, sulfonates? alkyl, aryl sulphonates and sulphonates of olefins, sulphates and sulphates of alkyl, olefins, ether and monoglycerides; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides and polyoxyethylene-1-enopolypropylene copolymers; amphoteric detergents, for example alkyl β-amino propionates and 2-alkyl imidazoline quaternary ammonium salts, as well as mixtures.

The parenteral compositions of the present invention typically contain from about 0.5% to about 25% by weight of active ingredient in solution. Preservative agents and agents. In order to minimize or eliminate irritation at the injection site, these compositions may contain a nonionic surfactant having a hydrophilic-1-phosphate (HLB) equilibrium of from about 12 to about 17 The amount of surfactant in these compositions ranges from about 5% to about 15% by weight. The surfactant may be a single component with the abovementioned HBL or may be a mixture of two or three components with the appropriate HBL ,

Illustrative surfactant agents used in the parenteral compositions are those belonging to the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and high molecular weight condensates of ethylene oxide with a hydroxyl base obtained by condensation of Oxy of propylene with propylene glycol,

The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. These suspensions may be prepared according to standard methods using suitable dispersing or wetting agents and suspending agents such as, for example, carboxymethylcellulose, sodium, methylcellulose, hydroxypropylmethylcellulose, and alginate. sodium, polyvinylpyrrolidone, gum tragacanth and acacia gum; dispersing agents or humectants which may constitute a naturally occurring phosphatide such as lecithin, or a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example heptadecaethylene oxycetanol, a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of a Ethylene oxide with a partial ester derived from a fatty acid e.g. of a hexitol anhydride, for example, polyoxyethylene sorbitan monooleate

The suspensions may also contain one or more stabilizing agents, for example ethoxylated or n-propyl oxyhydroxybenzoate; one or more coloring agents; one or more bulking agents; one or more sweetening agents such as sucrose or saccharin.

The oily suspensions may be prepared by suspending the active ingredient in a vegetable oil such as, for example, peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain an agent thickener such as, for example, beeswax, hard paraffin or cetyl alcohol. Sterile injectable preparations may also be made up of a sterile injectable solution or a sterile injectable suspension in one embodiment. or parenterally compatible and non-toxic diluent. Solvents or diluents which may be used are, for example, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending agents,

To this end, any fixed light oil may be used including synthetic moieties or diglycerides. In addition, fatty acids, such as oleic acid,

A composition of the present invention may also be administered in the form of suppositories for the rectal administration of the drug. These compositions may be prepared by mixing the drug with the appropriate non-irritating excipient, solid at ordinary temperatures plus liquid at rectal temperature and which therefore fuses into the rectum to release the drug. These substances are, for example, cocoa butter and polyethylene glycol,

The dispersible powders and granules are suitable for preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing agent or a wetting agent, a suspending agent and one or more preservatives. Dispersion, wetting and suspending agents are exemplified by those which have previously been referred to, Other excipients, for example, sweetening,

may also be present, as discussed above.

The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Emulsifiers Suitable natural gums may be naturally occurring gums such as acacia gum and gum tragacanth, [2] naturally occurring phosphatides such as soybean and licitin, [31 esters or esters derived from fatty acids and anhydrides of bexitol, for example, sorbitan monooleate, [4] condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may further contain sweetening and flavoring agents,

Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. These compositions may further contain a demulcent and preservative agents, flavorants and coloring agents,

The compounds of the present invention may also be administered topically, i.e. by an external application to the skin or mucosa, in compositions in the form of ointments, creams, lotions, gels, jellies, patches, powders, taplasmas or folders. The compositions for topical application of the compounds of the present invention may be prepared following standard methods and established procedures such as those described in Remington's Pharmaceutical Sciences, (Arthur OSol, Editor,

Easton, Pennsylvanis, Mach Publisfting Company, 16 " edition, 1980.

The compositions of this invention may also contain other conventional pharmaceutical acceptable composition compositions, generally referred to as carriers or diluents, if necessary or appropriate. Any of the compositions of the present invention may be preserved by addition of an antioxidant agent such as ascorbic acid or other suitable preservative agents.

Conventional processes for the preparation of such compositions may be used in the form of dosage forms.

The specific examples which follow are set forth to exemplify the compositions of this invention but are not to be construed as limiting their scope in any sense,

Example 4

A tablet is prepared from: 1-C2-furanylethyl) -1H-pyrrole-2-carboxylic acid 25 mg mg starch 40 mg talc 10 mg magnesium stearate 10 mg-

Example 5

Prepare a capsule from; 1-ΖΊ - (4-t-butyl) phenylmethyl] -1H-pyrrole-2-carboxylic acid 400 mg talc 40 mg sodium carboxymethyl cellulose 40 mg starch 120 mg

Example 6

A cream is prepared from; 1-yl) -1'-biphenyl-4-ylmethyl] -H-pyrrole-2-carboxylic acid 4.0 g of cetyl alcohol 7.0 g of glycerol monostearate PEG4Q 8.0 g of diglycol e.stearate 6.0 g polytetraglycol 400 37.5 g purified water 37.5 g the non-aqueous phase ingredients were added and heated under stirring at 60Â ° C and the composition of the present invention was added which was mixed until distilled or to dissolve,. Purified water was added at 60 ° C and the aqueous phase was added with stirring. The resulting emulsion was cooled to room temperature under continuous stirring,

The compounds of formula X may also be used in the form of free acids or in compositions as research and diagnostic elements or as analytical references or standards, etc. Therefore, the present invention includes compositions containing an inert carrier and an effective amount of a compound of formula I or a salt thereof. An inert carrier, and any substance which does not react with the carrier compound, carrier, carrier, " identifiable substance " and the like for the carrier compound. An effective amount of compound " the amount which it performs in an undesirable manner or produces a result or exerts an influence on the particular process to be carried out, in the subject matter which may be present invention without invention as is apparent to a person skilled in making changes or modifications to spirit withdrawal or scope of this has been described.

Claims (9)

A process for the preparation of compounds of general formula X represents a phenyl, naphthyl or biphenyl group each optionally having one, two or three substituents selected from alkyl groups, provided that the chain does not represent a methyl or C2 group when X represents an unsubstituted phenyl radical or X represents an unsubstituted naphthyl radical and provided that the substituent does not represent a 4-methyl group when X represents a substituted phenyl radical and the C1-6 chain represents an ethyl group; or a thiophenyl or furanyl group each optionally having a single substituent selected from C 1-4 alkyl having the proviso that the chain does not represent a methyl group when X represents an unsubstituted furanyl radical or salts thereof , characterized in that a compound of the general formula X - (x - 6) - n - 2 in which X and m are as defined above with 2,5-dimethyloxytetrahydrofuran and glacial acetic acid are subjected to reflux in order to subject the resulting product to a acylation of Friedel-Krafts with a compound of general formula (CY'3 CO) in which Y 'represents a fluorine, chlorine or bromine atom, of refluxing the mixture of the acylated product in alcohol with sodium or potassium hydroxide and water, and finally acidifying the solution and separating the compound of formula I * 9. 2. A process according to claim 1 for the preparation of compounds of general formula I in which the C1-6 chain comprises one, two or three carbon atoms, characterized in that correspondingly substituted starting compounds are used. 3. A process as claimed in claim 1 for the preparation of compounds of general formula I in which the chain comprises one, two or three carbon atoms and X represents optionally a substituted phenyl radical, correspondingly substituted starting compounds. 4. A process according to claim 1 for the preparation of compounds of general formula I in which the chain comprises one, two or three carbon atoms and X represents an unsubstituted furan or thiophenyl radical, characterized in that compounds correspondingly substituted initials. 5. A process according to claim 1 for the preparation of compounds of the general formula I in which the chain has one, two or three carbon atoms and X represents an unsubstituted biphenyl radical, characterized in that the starting compounds substituted. -amide 6. A process as claimed in claim 1 for the preparation of the acid 1 - " 3- (2-furanyl) propyl] -1H-pyrrole-2-carboxylic acid, characterized in that correspondingly substituted starting compounds are used. 7. A process according to claim 1 for the preparation of 1- (3-furanylmethyl) -1H-pyrrole-2-carboxylic acid, characterized in that correspondingly substituted starting compounds are used. 8. A process according to claim 1 for the preparation of 1- (phenylmethyl) -1H-pyrrole-2-carboxylic acid characterized in that correspondingly substituted starting compounds are used. 9. A compound according to claim 1 for the preparation of 1 - [(1'-biphenyl) -4-ylmethyl] -1H-pyrrole-2-carboxylic acid, correspondingly substituted starting compounds, Lisbon, January 30, 1990 The Official Federal Property Agent